Mycobacterium tuberculosis (Mtb) extracellular DNA (eDNA) gains access to the host cell cytosol via the ESX-1 secretion system. It is puzzling that this eDNA of Mtb does not induce activation of the AIM2-inflammasome since AIM2 recognizes cytosolic DNA. Here we show that non-virulent mycobacteria such as M. smegmatis induce AIM2-inflammasome activation, which is dependent upon their strong induction of IFN-β production. In contrast, Mtb, but not an ESX-1 deficient mutant, inhibits the AIM2-inflammasome activation induced by either M. smegmatis or transfected dsDNA. The inhibition does not involve changes in host cell AIM2 mRNA or protein levels but led to decreased activation of caspase-1. We furthermore demonstrate that Mtb inhibits IFN-β production and signaling, which was partially responsible for the inhibition of AIM2 activation. In conclusion, we report a novel immune evasion mechanism of Mtb that involves the ESX-1-dependent, direct or indirect, suppression of the host cell AIM2-inflammasome activation during infection.

The production of IL-1β during the infection with Mycobacterium tuberculosis (Mtb) is important for successful host immune defense. In macrophages and dendritic cells the host cell inflammasome is crucial for generation of secreted IL-1β in response to Mtb infections. In these cell types Mtb infection only activates the NLRP3-inflammasome. New reports demonstrate that nitric oxide has an important function in the negative regulation of the NLRP3-inflammasome to reduce tissue damage during Mtb infections. The type I interferon, IFN-β, is induced after Mtb infections and can also suppress NLRP3-inflammasome activation. In contrast, IFN-β increases activity of the AIM2-inflammasome after infection with intracellular pathogens such as Francisella tularensis and Listeria monocytogenes. Recent results demonstrate that non-tuberculous mycobacteria but not virulent Mtb induce the AIM2-inflammasome in an IFN-β dependent matter. Indeed, Mtb inhibits AIM2-inflammasome activation via its ESX-1 secretion system. This novel immune evasion mechanism may help Mtb to allow the induction of low levels of IFN-β to suppress the NLRP3-inflammasome without activating the AIM2-inflammasome.

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The type I IFNs (IFN-a and-b) are important for host defense against viral infections. In contrast, their role in defense against nonviral pathogens is more ambiguous. In this article, we report that IFN-b signaling in murine bone marrow-derived macrophages has a cell-intrinsic protective capacity against Mycobacterium tuberculosis via the increased production of NO. The antimycobacterial effects of type I IFNs were mediated by direct signaling through the IFN-a/b-receptor (IFNAR), as Abmediated blocking of IFNAR1 prevented the production of NO. Furthermore, M. tuberculosis is able to inhibit IFNAR-mediated cell signaling and the subsequent transcription of 309 IFN-b-stimulated genes in a dose-dependent way. The molecular mechanism of inhibition by M. tuberculosis involves reduced phosphorylation of the IFNAR-associated protein kinases JAK1 and TYK2, leading to reduced phosphorylation of the downstream targets STAT1 and STAT2. Transwell experiments demonstrated that the M. tuberculosis-mediated inhibition of type I IFN signaling was restricted to infected cells. Overall, our study supports the novel concept that M. tuberculosis evolved to inhibit autocrine type I IFN signaling to evade host defense mechanisms.

The synthesis of acyclic cucurbit[n]uril dendrimers G1 – G3 that bear four dendrons on their aromatic sidewalls via thiolate SN2 chemistry is reported. G1 – G3 are polycationic and can bind to pEGFP plasmid DNA as shown by dynamic light scattering (DLS), gel electrophoresis, and scanning electron microscopy (SEM). The gene delivery ability of G1 – G3 is presented.

We examined geographic variation within the Ashy Darter, Etheostoma cinereum, of the mitochondrially enconded cyto-chrome b gene (cyt b) and nuclear recombination activation gene 1 (RAG1) as well as pigmentation, 6 meristic variables,and 20 morphometric variables for patterns indicative of speciation within the complex. Four geographically disjunct en-tities were identified by at least one of the datasets corresponding to the Cumberland, Duck, Elk, and upper Tennesseeriver systems. Monophyly of cyt b and RAG1 sequences, modal meristic differences, moderate morphometric divergence,and unique pigmentation in specimens from the Cumberland River suggest this entity represents an evolutionary speciesunder many different species concepts and is described herein as Etheostoma maydeni. Other populations exhibit varyingdegrees of divergence in the different datasets and have conflicting relationships in phylogenetic analyses using cyt b andRAG1 sequences, leaving the evolutionary history and taxonomic status of the Duck, Elk and upper Tennessee populations unclear.

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